DESCRIPTION (From the applicant's abstract): This K08 application serves as a natural extension of my longstanding interest and background in basic neuroscience research, with special attention to disorders involving mental health. Current postdoctoral training under the Howard Hughes Postdoctoral Research Fellowship for Physicians in the laboratory of Neil Aronin, MD, has updated and developed my skills in molecular biology, neurobiology, and protein chemistry in the study of mechanisms of neuronal death in Huntington's disease (HD). The period of K08 support will permit me to develop in new scientific directions, entering the field of signal transduction as related to apoptotic neurodegeneration. Under the joint mentorship of Dr. Aronin and Dr. Roger Davis, an established leader in the signaling field, I will learn new techniques and approaches to study signal transduction pathways involved in cell dysfunction and death in HD and other neurodegenerative illnesses. By learning hands-on in Dr. Davis's laboratory as well as participating in discussions and laboratory meetings, I will gain invaluable background and experience in this rapidly-changing and complex field. In addition, I intend to supplement my research activities with formal didactic training in advanced molecular biology and cell biology. This immediate plan will provide me the experience and expertise necessary for success in my long-term career goal of independent research on cell pathways involved in processing of abnormal proteins and induction of pro-apoptotic signaling cascades in HD and other degenerative neuropsychiatric illnesses. My proposed K08 research revolves around the hypothesis that neurons expressing the HD mutation are especially vulnerable to injury and death due to excitotoxicity and mitochondrial energy impairment. I will focus on effects in cultured cortical neurons, an especially vulnerable cell population in HD, second only to striatal medium spiny neurons. Using glutamatergic agonists and mitochondrial inhibitors, I will assess effects on cell survival, induction of apoptosis, and activation of the c-Jun N-terminal kinase (JNK) signal transduction system, a kinase cascade stimulated by a variety of cell stressors and a key mediator of apoptosis. These studies will provide important insights into the cellular mechanisms leading to cortical neuronal death due to the interrelated effects of glutamatergic excitotoxicity and energy impairment, which are thought to be central to the pathophysiology of HD.